Piezoelectric dispenser with a longitudinal transducer and replaceable capillary tube

ABSTRACT

A dispenser and methods for transferring liquids are disclosed. The dispenser may include a capillary tube with tip having an aperture, a piezoelectric actuator coupled to the capillary tube at a location. Actuation of the piezoelectric actuator causes a pressure wave to propagate along the capillary tube toward the tip such that radial motion at the location is transmitted as distally extending axial motion of the tip, thereby causing a droplet of a predetermined volume to be ejected from the aperture. In some embodiments, the capillary tube has a modulus of elasticity in a range which dampens acoustical noise from the actuation and provides single drop stability over a range of drop sizes.

BACKGROUND

Disclosed embodiments relate in general to systems and methods foracquiring and dispensing predetermined volumes of liquids and, moreparticularly but not exclusively, to piezoelectric devices and methodsfor dispensing and transferring small volumes of fluid in the form ofsingle droplets or drops, typically ranging in volume from picoliters tonanoliters.

Conventional piezoelectric dispensing devices have a tube that istypically entirely surrounded by and bonded to a piezoelectric actuatorto produce droplets. Activation of the piezoelectric actuator transmitsacoustic pressure into and through the liquid in the tube. The acousticpressure propagates through the liquid and to a dispensing opening ofthe tube. This results in ejection of a liquid drop from the device.

Such conventional devices have several disadvantages. One is that theiroperation is highly dependent on the characteristics and properties ofthe particular liquid to be dispensed. Thus, disadvantageously,dispensing parameters such as droplet size cannot be independentlycontrolled and various compensative measures have to be taken which canincrease cost and reduce efficiency.

Moreover, to transmit pressure to the liquid in the tube to dispense adroplet a relatively force (energy) needs to be imparted by thepiezoelectric actuator. This can not only raise system and operationalcosts, but can undesirably lead to degradation, damage and denaturing ofthe liquid. Also, this further limits the actuator's operationalfrequency since higher frequencies may also cause liquid degradation,damage or denaturing. The transmission of a relatively high pressure tothe liquid can lead to the formation of bubbles in the liquid which canundesirably cause dispensing inaccuracies, among other undesiredoperational complications.

Another disadvantage of such conventional devices is that thepiezoelectric actuator is structurally bonded to the tube. Since manyapplications of dispensing using such devices involve the use ofmultiple liquids, such as, but not limited to, the fields of genomicsand proteomics, among others, these devices fail to provide an efficientand cost-effective approach to a system involving handling of multipleliquids in small quantities, for example, biological and chemicalreagents.

Typically, there are two options, neither one desirable, of addressingthis situation. One is to simply discard the piezoelectric-tube deviceand use a new one for further processing of other liquids. Thepiezoelectric actuator is a relatively expensive component, anddiscarding it after a single use disadvantageously adds to thecost—given that some of the applications can involve the handling ofhundreds or thousands, if not more, different liquids.

The second option is to rinse and clean the dispensing tube after eachuse to prevent contamination. Firstly, this undesirably adds additionalsteps to the liquid handling in terms of both efficiency and cost of theoverall process. Secondly, in spite of any stringent rinsing or cleaningroutines the risk of cross contamination always exists.

SUMMARY

It is one advantage of certain embodiments to provide systems, devicesand methods comprising a piezoelectric dispenser or dispensing devicethat is configured so that the dispensing tube and piezoelectricactuator are separable. This allows for the removal and replacement ofthe tube for subsequent use. Desirably, such embodiments with aseparable tube, not only eliminate the need for cleaning and the risk ofcontamination from left over material transferred from prior use, butalso advantageously increase system efficiency and are cost-effective.

Certain embodiments provide longitudinal transducers or transmissiondevices, and related methods of operation, for transmission orconversion of radial motion to axial or longitudinal motion. Thelongitudinal transducer generally comprises a piezoelectric actuatorcoupled to a tube or the like. Actuation of the piezoelectric actuatorby a voltage pulse causes radially inwards motion of the tube andgenerates an acoustic pressure or stress wave through the wall of thetube which results in axial or longitudinal motion, or displacement ofthe tube wall at the distal tip of the tube. In other words, actuationof the actuator causes the distal tip to axially extend and then axiallyretract back to its original form on deactivation of the actuator and/orits pulse, that is, the distal tip oscillates. When multiple pulses areprovided, the distal tip oscillates in response to each pulse cycle.

Certain embodiments provide systems, devices and methods comprising aliquid dispenser or dispensing device that includes and/or incorporatesa longitudinal transducer with a piezoelectric actuator, as disclosedherein, for transmission or conversion of radial motion to axial orlongitudinal motion to a dispensing tube thereby causing a droplet to bedispensed from an aperture or outlet orifice at the distal tip of thetube. Some of these embodiments are configured so that the dispensingtube and piezoelectric actuator are separable, as disclosed herein.

Some advantages of the dispensing embodiments utilizing a longitudinaltransducer include, but are not limited to: since minimal or negligibleforce, pressure is imparted to the liquid in the dispensing tube severalof the problems associated with conventional dispensing devices, asdescribed above, are mitigated or substantially eliminated—such asgreater dispensing flexibility and independence substantially regardlessof the liquid properties or characteristics, general avoidance ofproblems associated with degradation, damage and denaturing of theliquid and undesirable bubble formation, and ability to operate athigher frequencies, among others.

One exemplary application of the dispensers or dispensing devicesdisclosed herein relates to the production of DNA arrays for geneticengineering uses, wherein a high clone density is achieved by means of asmall droplet size, for which piezoelectric operated dispensers inaccordance with disclosed embodiments are particularly suitable.Embodiments can be particularly advantageous for production of workingcopies for screening processes, for example, in the pharmaceuticalindustry in production of microarrays or for the production of multiplyassays.

Some embodiments provide a piezoelectric micro-dispensing device,apparatus or system that enables automatic or manual transfer of smallvolumes of liquids typically ranging in volume from picoliters tonanoliters. Advantageously, the device can allow for the disposal of thedispensing tube while permitting reuse of the piezoelectric actuator.Alternatively, or in addition, the device can desirably further comprisea longitudinal transducer for transmission or conversion of radialmotion to axial or longitudinal motion to a dispensing tube therebyallowing for a liquid droplet to be dispensed from an aperture at thedistal tip of the tube.

In some embodiments, the dispenser includes a main body portion ormounting bracket and comprises a tube which includes a dispensing nozzleat one end of the tube. The tube can comprise, for example, but notlimited to, a glass capillary tube. The dispenser can further comprise apiezoelectric clamp for clamping to an outer circumferential orperipheral surface of the tube. The piezoelectric clamp can comprise twoopposing jaws or clamping or supporting structures. The first jaw caninclude a piezoelectric actuator or transducer and the second jaw caninclude a preloading, clamping, retaining or biasing mechanism, device,assembly or structure to apply a predetermined reactive force to thetube.

In some embodiments, the preloading mechanism, device, assembly orstructure includes a preloading screw. In other embodiments, thepreloading mechanism, device, assembly or structure includes apreloading assembly of a spring, such as a leaf spring or the like, amass providing ball or the like, and a knob or lever that is utilized toactuate or release the preloading.

In some embodiments, the clamp is operable to hold the tube in place andto transmit acoustic pressure to the clamped area of the tube onactuation of the piezoelectric actuator or transducer. Acoustic pressureor stress propagates longitudinally from the clamped area through thetube and toward the nozzle whereat axial displacement at the distal tipof the tube and/or transmission of acoustic pressure to the fluid in thearea of the nozzle propels, ejects or dispenses a droplet of fluidhaving a predetermined volume or quantity, due at least in part to thesolid-fluid interaction in the area of the nozzle. Thus, a wave passinglongitudinally through the tube wall provides for transmission orconversion of tube radial motion to axial or longitudinal motion to thetube tip thereby allowing for a liquid droplet to be dispensed from anaperture at the tip of the tube. In some embodiments, this wave has agenerally sinusoidal or cosine waveform, profile or configuration.

In some embodiments, following each use of dispensing a particularliquid the clamp may be released to replace the tube. As such, the tubemay be disposed following each use with a particular liquid while thepiezoelectric clamp is reused with another tube. Advantageously, thisprovides an economic utilization of the piezoelectric or piezoceramicactuator or transducer. In addition, and desirably, such an arrangementof a dispenser eliminates the need for cleaning the tube and the risk ofcross contamination from left over material transferred from the prioruse of the device.

Single droplets having a volume in the range from a few picoliters to afew nanoliters can be accurately and reliably dispensed, for example, inthe range from about 50 picoliters to about 1,000 picoliters (1nanoliter), including all values and sub-ranges therebetween.

In addition to dispensing droplets, fluid may also be acquired oraspirated into the tube. The fluid samples can be acquired, aspirated ordrawn up into the tube by dipping its tip into a fluid source andapplying vacuum, for example, using a pump or the like. The size of thetube can vary, as needed or desired, but is typically sufficiently smallto draw fluid from a standard microtiter or micro-well plate, forexample, one having a square or diametric dimension of about 5 mm orless.

The piezoelectric actuator, in some embodiments, comprises a monolithicco-fired ceramic stack which expands and contracts under the input of apulsed DC voltage. The stack can be a linear or longitudinal stack whichexpands and contracts generally linearly or longitudinally in thedirection of the stack. The piezoelectric or piezoceramic stack iscapable of applying a predetermined force in the radial directionagainst the tube. To prevent breakage of the tube, the tube may beprovided with a sleeve, for example, a plastic or metal sleeve, whichsubstantially evenly distributes the force around the clamping area ofthe tube.

Some embodiments are directed to systems, devices, methods, andtechniques are provided, for acquiring and dispensing predeterminedvolumes of liquids and, in particular, to a unique piezoelectricdispensing device for acquiring and dispensing of volumes of liquids,specifically, but not exclusively, for use in dispensing andtransferring of small volumes of fluid in, for example, automatic ormanual production of DNA arrays and assays, wherein droplets aredispensed in a single drop format with volumes, for example, rangingfrom about a few picoliters to several nanoliters. The dispensingdevices or dispensers can advantageously utilize a disposable capillarytube assembly while desirably retaining the piezoelectric actuator ortransducer for subsequent further uses, thereby mitigating thepossibility of cross contamination of fluids and providing an economicaland cost effective approach with reuse of the piezoelectric actuator ortransducer for further operation such as with a variety of liquids to bedispensed and transferred. The systems or devices can incorporate aunique longitudinal transducer that transmits or converts radial tubedisplacement or motion to controlled axial or longitudinal displacementmotion of a distal tip of the tube.

In some embodiments of the piezoelectric dispenser disclosed herein, thepiezoelectric device does not completely surround, encircle orcircumscribe the outer periphery of the dispensing tube, but does soonly partially. In other words, the piezoelectric device is on a firstside of the tube while the preloading device, when included, is on asecond substantially opposed second side of the tube. In otherembodiments, such as those not incorporating a configuration in whichthe dispensing tube is separable from the piezoelectric device, thepiezoelectric device can substantially completely surround, encircle orcircumscribe the outer periphery of the dispensing tube, or it can do soonly partially.

In accordance with some embodiments, a dispenser for transferring apredetermined quantity of a liquid is provided. The dispenser generallycomprises a tube, a piezoelectric device and a preloading device. Thetube contains a liquid to be dispensed into or onto one or more targets.The piezoelectric device is selectively communicable with a first sideof the tube and is responsive to an applied signal, and the preloadingdevice is selectively communicable with a second side of the tube thatis generally disposed in opposition to the first side, thereby allowingfor separation of the tube and the piezoelectric device

In some embodiments, the piezoelectric device is configured such thatwhen actuated the piezoelectric device transmits a generally radialfirst force to the tube. Actuation of the piezoelectric actuator by avoltage pulse causes radially inwards motion of the tube and generatesan acoustic pressure or stress wave through the wall of the tube whichresults in axial or longitudinal motion or displacement of the tube wallat the distal tip of the tube thereby causing a droplet of predeterminedvolume to be ejected from the tube. The preloading device, whenincluded, can be configured to provide a generally reactive and opposedsecond force to the tube.

In accordance with some embodiments, a method of transferring apredetermined quantity of a liquid is provided. The method generallycomprises providing a tube with a liquid to be dispensed and apiezoelectric device in communication with the tube. The piezoelectricdevice is actuated such that a generally radial force is applied to thetube and which creates a longitudinal stress or pressure wave thatpropagates to and causes axial displacement of a distal tip of the tubeso as to eject a predetermined volume of the liquid. Advantageously, insome embodiments, the dispensing tube can be replaced with another tubefor dispensing of another liquid.

In some embodiments, the dispensing systems, devices and methodsdisclosed herein may be used for the delivery of surfactants toneonate/local anesthetic in laparoscopy. In some embodiments, thedispensing systems, devices and methods disclosed herein may be used forthe delivery of aerosolized pharmaceuticals to human or animal subjects.In some embodiments, the dispensing systems, devices and methodsdisclosed herein may be used for dispensing of chemicals formicroelectronic manufacturing. In some embodiments, the dispensingsystems, devices and methods disclosed herein may be used for printinginert inks onto surfaces, papers or the like, among others.

In accordance with some embodiments, a longitudinal transducer forconverting a radial displacement to an axial displacement is provided.The longitudinal transducer generally comprises a tube, a linear orlongitudinal piezoelectric actuator and an energy source. The tube has alength, a wall with a predetermined thickness, a lumen with apredetermined size or diameter, and a tip at a distal end of the tube.The linear or longitudinal piezoelectric actuator is clamped to the tubeat a location proximal of the tip. The energy source is configured toprovide at least one voltage pulse to the piezoelectric actuator.Actuation of the piezoelectric actuator causes a pressure wave topropagate from the proximal location of the tube toward the tip of thetube such that radial motion at the proximal location of the tube istransmitted as distally extending axial motion of the tip of the tube.

In one embodiment, the voltage pulse and configuration of the tube areselected such that a peak of the pressure wave is located substantiallyat the tip of the tube.

In accordance with some embodiments, a method of converting a radialdisplacement into an axial displacement is provided. The method involvesproviding a transducer that comprises a piezoelectric actuator which isresponsive to a voltage signal. The piezoelectric actuator is actuatedto provide a generally radial force to a tube of the transducer at aregion that is proximal to a distal end of the tube. Radial motion ofthe tube at the proximal region of the tube is converted to generallyaxial motion at the distal end of the tube.

In one embodiment, actuation of the piezoelectric actuator comprisesproviding at least one voltage pulse to the piezoelectric actuator.

In one embodiment, the piezoelectric actuator comprises a linear orlongitudinal piezoelectric actuator that is clamped to the tube.

In one embodiment, the axial motion comprises distal axial motion, andon deactivation of a pulse of the voltage signal the distal end of thetube is subjected to a motion in a proximal axial direction, therebyproviding an axial oscillation in response to at least one pulsedvoltage cycle.

In accordance with some embodiments, a dispenser for transferring apredetermined quantity of a liquid is provided. The dispenser generallycomprises a tube a piezoelectric actuator. The tube contains a liquid tobe dispensed into or onto one or more targets. The piezoelectricactuator is operatively coupled to the tube and is responsive to anapplied signal for dispensing one or more droplets of the liquid. Thetube and the piezoelectric actuator are separable such that the tube maybe replaced while allowing for the same piezoelectric actuator to beused with another tube for dispensing another liquid.

In one embodiment, the piezoelectric actuator is mounted on a first sideof the tube. In one embodiment, a preloading device is mounted on asecond side of the tube which is generally opposed to the first side. Inone embodiment, the preloading device comprises a screw. In oneembodiment, the preloading device comprises an actuable spring loadeddevice. In one embodiment, the preloading device is releasable to allowfor removal and replacement of the tube.

In one embodiment, actuation of the piezoelectric actuator causesconversion of a radial motion of the tube into an axial motion at a tipof the tube to cause a droplet of predetermined volume to be ejectedfrom the tip.

In one embodiment, the piezoelectric actuator is spaced from the tube bya sleeve attached to the tube.

In one embodiment, the tube is part of a replaceable assembly thatcomprises the tube and a sleeve that is bonded to the tube.

In one embodiment, the dispenser further comprises a first jaw and asecond jaw respectively engaged with the piezoelectric actuator and apreloading device. In one embodiment, the jaws comprise structures thatengage a sleeve that is attached to the tube at a predetermined numberof locations.

In one embodiment, a lumen of the tube has a generally annularconfiguration.

In one embodiment, the liquid to be dispensed within the tube is axiallybelow the location of the piezoelectric actuator.

In one embodiment, the tube has an aperture plate with a generallycurved funnel or conical configuration.

In one embodiment, the tube is part of a library of stored tubes withrespective fluids pre-filled therein to allow for dispensing of multipleliquids while utilizing the same piezoelectric actuator.

In one embodiment, the dispenser is provided in combination with a fluidsource that allows acquisition of liquid to be dispensed by thedispenser from the source.

In one embodiment, the dispenser is provided in combination with animaging system to visualize and analyze dispensed droplets.

In one embodiment, the dispenser is provided in combination with alibrary of stored fluid samples that are selectively loadable within thetube.

In one embodiment, the piezoelectric actuator comprises a linear orlongitudinal piezoelectric actuator that is clamped to the tube.

In accordance with some embodiments, a method of transferring apredetermined quantity of a liquid is provided. The method involvesproviding a tube from which a liquid is to be dispensed and a linear orlongitudinal piezoelectric actuator clamped to the tube. Thepiezoelectric actuator is actuated to eject a droplet of liquid from adistal tip of the tube. The tube is separated from the piezoelectricactuator and replaced with another tube for dispensing of another liquidwhile utilizing the same piezoelectric actuator.

In one embodiment, the tube is selected from a library of stored tubeswith respective liquids pre-filled therein.

In one embodiment, the liquid to be dispensed is aspirated from a fluidsource.

In one embodiment, a library of stored fluid samples that areselectively loadable within the tube is provided.

In one embodiment, a lumen of the tube has a generally annularconfiguration.

In one embodiment, actuation of the piezoelectric actuator causesconversion of a radial motion of the tube into an axial motion at a tipof the tube to cause a droplet of predetermined volume to be ejectedfrom the tip.

In accordance with some embodiments, a dispenser for transferring apredetermined quantity of a liquid is provided. The dispenser generallycomprises a longitudinal transducer, an aperture and a liquid. Thelongitudinal transducer generally comprises a tube and a piezoelectricactuator. The tube has a length, a wall with a predetermined thickness,a lumen with a predetermined size or diameter, and a tip at a distal endof the tube. The piezoelectric actuator is operatively coupled to thetube at a location proximal of the tip. The aperture is at the tip ofthe tube. The liquid is to be dispensed into or onto one or more targetsand is loaded within the tube. Actuation of the piezoelectric actuatorcauses a pressure wave to propagate from the proximal location of thetube toward the tip of the tube such that radial motion at the proximallocation of the tube is transmitted as distally extending axial motionof the tip of the tube, thereby causing a droplet of a predeterminedvolume to be ejected from the aperture.

In one embodiment, the piezoelectric actuator comprises a linear orlongitudinal piezoelectric actuator that is clamped to the tube.

In one embodiment, the dispenser further comprises an energy source thatis configured to provide at least one voltage pulse to the piezoelectricactuator

In one embodiment, the tube and the piezoelectric actuator areseparable.

In one embodiment, the tube is selected from a library of stored tubeswith respective liquids pre-filled therein.

In one embodiment, a lumen of the tube has a generally annularconfiguration.

In one embodiment, the dispenser is provided in combination with a fluidsource that allows acquisition of liquid to be dispensed by thedispenser from the source.

In one embodiment, the dispenser is provided in combination with alibrary of stored fluid samples that are selectively loadable within thetube.

In accordance with some embodiments, a method of transferring apredetermined quantity of a liquid is provided. The method involvesproviding a tube with a liquid to be dispensed. The tube comprises adistal end with a tip and an aperture thereat. A piezoelectric actuatoris provided in communication with the tube at a location proximal to thetip of the tube. The piezoelectric actuator is actuated such that apressure wave propagates from the proximal location of the tube towardthe tip of the tube and radial motion at the proximal location of thetube is transmitted as axial motion of the tip of the tube, therebycausing a droplet of a predetermined volume to be ejected from theaperture.

In one embodiment, the piezoelectric actuator comprises a linear orlongitudinal piezoelectric actuator that is clamped to the tube.

In one embodiment, the tube is replaced with another tube for dispensingof another liquid.

In one embodiment, the tube is selected from a library of stored tubeswith respective liquids pre-filled therein.

In one embodiment, the liquid to be dispensed is acquired from a fluidsource.

In one embodiment, a library of stored fluid samples that areselectively loadable within the tube is provided.

In one embodiment, a lumen of the tube has a generally annularconfiguration.

In one embodiment, the piezoelectric actuator is positioned axiallyabove the liquid in the tube.

In accordance with some embodiments, a longitudinal transducer forconverting a radial displacement to an axial displacement is provided.The longitudinal transducer generally comprises a tube, a linear orlongitudinal piezoelectric actuator and an energy source. The tubecomprises a generally rigid material and has a length, a wall with apredetermined thickness, a lumen with a predetermined size or diameter,and a tip at a distal end of the tube. The rigid material of the tubehas a modulus of elasticity greater than about 10 GPa. The linear orlongitudinal piezoelectric actuator is clamped to the tube at a locationproximal of the tip of the tube. The energy source is configured toprovide at least one voltage pulse to the piezoelectric actuator.Actuation of the piezoelectric actuator causes a pressure wave topropagate from the proximal location of the tube through the wall of thetube and toward the tip of the tube such that radial motion at theproximal location of the tube is transmitted as distally extending axialmotion of the tip of the tube.

In one embodiment, the rigid material of the tube has a modulus ofelasticity greater than about 50 GPa.

In one embodiment, an aperture is at the tip of the tube and a liquid tobe dispensed into or onto one or more targets, by the actuation of thepiezoelectric actuator, is contained in the tube. In one embodiment, thetube and the piezoelectric actuator are separable.

In accordance with some embodiments, a method of transferring apredetermined quantity of a liquid is provided. The method involvesproviding a flexible supply line. A liquid is supplied from the flexiblesupply line to a tube downstream of the flexible supply line. The tubecomprises a distal end with a tip and an aperture thereat. Apiezoelectric actuator is provided in communication with the tube at alocation proximal to the tip of the tube. The piezoelectric actuator isactuated such that a pressure wave propagates from said location of thetube toward the tip of the tube and radial motion at said location ofthe tube is transmitted as axial motion of the tip of the tube, therebycausing a droplet of a predetermined volume to be ejected from theaperture.

In one embodiment, the coupling between the tube and the flexible supplyline provides a self-aligning feature.

In one embodiment, the flexible supply line comprises a plastic orthermoplastic. In one embodiment, the flexible supply line comprisespolypropylene (PP). In one embodiment, the flexible supply linecomprises polyether ether ketone (PEEK).

In one embodiment, the flexible supply line has an inner diameter ofabout 750 μm or less. In one embodiment, the flexible supply line has aninner diameter of about 250 μm.

In one embodiment, the tube comprises an aperture plate that defines theaperture. In one embodiment, the aperture plate is gold plated. In oneembodiment, the aperture plate is electro-formed. In one embodiment, thegold plated aperture plate is coated with self assembled monolayer(SAM). In one embodiment, the self assembled monolayer comprises Poly(ETHYLENE GLYCOL) methyl ether thiol CH3O(CH2CH2O)Nch2ch2SH.

In accordance with some embodiments, a dispenser for transferring apredetermined quantity of a liquid is provided. The dispenser generallycomprises a longitudinal transducer, an aperture and a flexible supplyline. The longitudinal transducer generally comprises a tube and apiezoelectric actuator. The tube has a length, a wall with apredetermined thickness, a lumen with a predetermined size or diameter,and a tip at a distal end of the tube. The piezoelectric actuator isoperatively coupled to the tube at a location proximal of the tip. Theaperture is at the tip of the tube. The flexible supply line is locatedupstream of the tube and is configured to supply a liquid to the tubethat is to be dispensed into or onto one or more targets. The liquid isloaded within the tube. Actuation of the piezoelectric actuator causes apressure wave to propagate from the proximal location of the tube towardthe tip of the tube such that radial motion at the proximal location ofthe tube is transmitted as distally extending axial motion of the tip ofthe tube, thereby causing a droplet of a predetermined volume to beejected from the aperture.

In one embodiment, the coupling between the tube and the flexible supplyline provides a self aligning feature.

In one embodiment, the flexible supply line comprises a plastic orthermoplastic. In one embodiment, the flexible supply line comprisespolypropylene (PP). In one embodiment, the flexible supply linecomprises polyether ether ketone (PEEK).

In one embodiment, the flexible supply line has an inner diameter ofabout 750 μm or less. In one embodiment, the flexible supply line has aninner diameter of about 250 μm.

In one embodiment, the tube comprises an aperture plate that defines theaperture. In one embodiment, the aperture plate is gold plated. In oneembodiment, the aperture plate is electro-formed. In one embodiment, thegold plated aperture plate is coated with self assembled monolayer(SAM). In one embodiment, the self assembled monolayer comprises Poly(ETHYLENE GLYCOL) methyl ether thiol CH3O(CH2CH2O)Nch2ch2SH.

In another embodiment, a dispenser for transferring a predeterminedquantity of a liquid is disclosed. The dispenser includes a longitudinaltransducer, including: a capillary tube having a tip at the distal end;a piezoelectric actuator operatively coupled to the capillary tube at alocation proximal of the tip; an aperture at the tip of the tube; and aflexible supply line located upstream of the capillary tube andconfigured to couple to and supply the liquid to the capillary tube;where actuation of the piezoelectric actuator causes a pressure wave topropagate from said location of the capillary tube toward the tip of thecapillary tube such that radial motion at said location of the capillarytube is transmitted as distally extending axial motion of the tip of thecapillary tube, thereby causing a droplet of a predetermined volume tobe ejected from the aperture; and wherein the capillary tube has amodulus of elasticity in a range of about 0.1 to 9.0×10⁶ psi, and insome cases 0.1 to 1.5×10⁶ psi, thereby dampening acoustical noise fromthe actuation and providing single drop stability over a range of dropsizes from about 50 to 1300 pL.

The coupling between the capillary tube and the flexible supply line mayprovide a self-aligning feature.

The operative coupling between the capillary tube and the piezoelectricactuator may be configured to allow replacement of capillary tubes andis adjustable to provide sufficient mechanical stability to reducevariations in droplet volumes between capillary tubes. In oneembodiment, the operative coupling between the capillary tube and thepiezoelectric actuator is a double V clamp.

In one embodiment, the capillary tube may include polyether ether ketone(PEEK).

In one embodiment, the capillary tube may include an aperture plate thatdefines the aperture. The aperture plate may be gold-plated nickel orsapphire.

A method for transferring a predetermined quantity of a liquid isdisclosed in accordance with another embodiment. The method includes:coupling a flexible supply line to a capillary tube using aself-aligning feature; supplying liquid from the flexible supply line tothe capillary tube, wherein the capillary tube comprises a distal endwith a tip and an aperture thereat; coupling a piezoelectric actuator tothe capillary tube at a location along the capillary tube, wherein thecoupling between the piezoelectric actuator and the capillary tube isconfigured to allow replacement of capillary tubes and is adjustable toprovide substantially uniform mechanical stability between thepiezoelectric actuator and replaceable capillary tubes; actuating thepiezoelectric actuator such that a pressure wave propagates from saidlocation along the capillary tube toward the tip of the capillary tubeand radial motion at said location is transmitted as axial motion of thetip, thereby causing a droplet of a predetermined volume to be ejectedfrom the aperture; wherein the capillary tube has a modulus ofelasticity in a range of about 0.1 to 9.0×10⁶ psi, and in some cases 0.1to 1.5×10⁶ psi, thereby dampening acoustical noise from the actuationand providing single drop stability over a range of drop sizes fromabout 50 to 1300 pL.

In a variation, the method may further include adjusting the couplingbetween the piezoelectric actuator and the capillary tube to reducevariation in droplet volume between capillary tubes.

In another variation, the method may further include adjusting apiezoelectric voltage, a charge resistor, or both a voltage and a chargeresistor to enable dispensing a range of liquid viscosities at the samepredetermined droplet volumes.

For purposes of summarizing the disclosure, certain aspects, advantagesand novel features have been described herein above. Of course, it is tobe understood that not necessarily all such advantages may be achievedin accordance with any particular embodiment. Thus, aspects of thedisclosure may be embodied or carried out in a manner that achieves oroptimizes one advantage or group of advantages as taught or suggestedherein without necessarily achieving other advantages as may be taughtor suggested herein.

All of these embodiments are intended to be within the scope of thepresent disclosure. These and other embodiments will become readilyapparent to those skilled in the art from the following detaileddescription having reference to the attached figures.

BRIEF DESCRIPTION OF THE DRAWINGS

Having thus summarized the general nature of the present disclosure andsome of its features and advantages, certain embodiments andmodifications thereof will become apparent to those skilled in the artfrom the detailed description herein having reference to the figuresthat follow, of which:

FIG. 1A is a simplified schematic view of a piezoelectric fluiddispensing system illustrating features and advantages in accordancewith certain embodiments.

FIG. 1B is a simplified schematic view of a longitudinal transducer fortransmission or conversion of radial movement to axial movementillustrating features and advantages in accordance with certainembodiments.

FIG. 2 is a simplified schematic side view of a piezoelectric fluiddispenser in an unclamped position illustrating features and advantagesin accordance with certain embodiments.

FIG. 3 is a simplified schematic side view of the piezoelectric fluiddispenser of FIG. 2 in a clamped position illustrating features andadvantages in accordance with certain embodiments.

FIG. 4A is a simplified schematic top view of the piezoelectric fluiddispenser of FIG. 3 illustrating features and advantages in accordancewith certain embodiments.

FIG. 4B is a simplified schematic top view of the piezoelectric fluiddispenser illustrating another embodiment of the double V clampconfiguration of FIG. 4A.

FIG. 5A is a simplified schematic side view of a piezoelectric fluiddispenser incorporating a tube with an annular gap illustrating featuresand advantages in accordance with certain embodiments.

FIG. 5B is a simplified schematic side view of a piezoelectric fluiddispenser incorporating a tube showing another configuration of thedispenser shown in FIG. 5A.

FIG. 6A is a simplified schematic side view of a piezoelectric fluiddispenser incorporating a mounting bracket suitable for dispensing offluid in the production of dot arrays or the like illustrating featuresand advantages in accordance with certain embodiments.

FIG. 6B is a simplified schematic side view of a piezoelectric fluiddispenser incorporating a mounting bracket suitable for dispensing offluid in the production of dot arrays or the like illustrating anotherconfiguration of the dispenser shown in FIG. 6A.

FIG. 7 is a simplified schematic side view of a piezoelectric fluiddispenser with multiple clamping devices illustrating features andadvantages in accordance with certain embodiments.

FIG. 8A is a simplified perspective view of a piezoelectric fluiddispenser incorporating a spring biased preloading mechanismillustrating features and advantages in accordance with certainembodiments.

FIG. 8B is a simplified perspective view of a piezoelectric fluiddispenser illustrating an alternative configuration of the dispenser inFIG. 8A.

FIG. 9A is a simplified exploded perspective view of the piezoelectricfluid dispenser of FIG. 8A illustrating features and advantages inaccordance with certain embodiments.

FIG. 9B is a simplified exploded perspective view of the piezoelectricfluid dispenser of FIG. 8B, illustrating features and advantages of thatalternative configuration.

FIG. 10 is a simplified sectional perspective view of the piezoelectricfluid dispenser of FIG. 8A illustrating features and advantages inaccordance with certain embodiments.

FIG. 11A is a simplified sectional side view of the piezoelectric fluiddispenser of FIG. 8A illustrating features and advantages in accordancewith certain embodiments.

FIG. 11B is a simplified sectional side view of the piezoelectric fluiddispenser of FIG. 8B, illustrating features and advantages of thatalternative configuration.

FIG. 12A is a simplified exploded perspective view of a capillary tubeassembly of a piezoelectric fluid dispenser illustrating features andadvantages in accordance with certain embodiments.

FIG. 12B is a simplified exploded perspective view of a capillary tubeassembly of a piezoelectric fluid dispenser illustrating an alternativeconfiguration from that shown in FIG. 12A.

FIG. 13A is a simplified front or rear planar view of the capillary tubeassembly of FIG. 12A illustrating features and advantages in accordancewith certain embodiments.

FIG. 13B is a simplified front or rear planar view of the capillary tubeassembly of FIG. 12B illustrating features of that alternativeconfiguration.

FIG. 14A is a simplified sectional view of FIG. 13A illustratingfeatures and advantages in accordance with certain embodiments.

FIG. 14B is a simplified sectional view of FIG. 13B illustratingfeatures of that alternative configuration.

FIG. 15 is a graph plotting the data from Table II.

FIG. 16 is a graph plotting the data from Table III.

DETAILED DESCRIPTION

The embodiments described herein relate generally to systems and methodsfor acquiring and non-contact dispensing of predetermined volumes ofliquids and, in particular, to unique piezoelectric dispensing devicesfor acquiring and dispensing of volumes of liquids, specifically, butnot exclusively, for use in dispensing and transferring small volumes offluid in, for example, automatic production of DNA arrays or multipleassays, wherein droplets are dispensed in a single drop format withvolumes, for example, ranging from about a few picoliters to severalnanoliters. Embodiments of the dispensing devices advantageously utilizea disposable, removable or separable capillary tube assembly whiledesirably retaining the piezoelectric actuator or transducer forsubsequent further uses, thereby mitigating the possibility of crosscontamination of fluids and providing an economical and cost effectiveapproach with reuse of the piezoelectric actuator or transducer forfurther operation such as with a variety of liquids to be dispensed andtransferred.

While the description sets forth various details of certain embodiments,it will be appreciated that the description is illustrative only andshould not be construed in any way as limiting. Furthermore, variousapplications, and modifications thereto, which may occur to those whoare skilled in the art, are also encompassed by the general conceptsdescribed herein.

Turning now to the drawings, FIG. 1A illustrates a liquid dispensing(and aspirating or acquiring) system 10 for fluid handling and transferin accordance with some embodiments. The system 10 generally comprises apiezoelectric dispensing device or dispenser 100 for dispensing singleliquid droplets or drops 12 onto or into one or more targets orsubstrates 14 from a fluid or liquid source 16, such as a vessel orvial, among others, that holds or contains a liquid 18 to be dispensed

The source 16 is in fluid communication with the dispensing device ordispenser 100 via, for example, a flexible tube or the like. Therelative Z-direction positioning between the source 16 and the dispenser100 (and its capillary tube) is selected giving consideration to abalance between the hydrostatic pressure head on the capillary tube,capillary forces and surface tension of the liquid 18 so that no liquidis emitted from the dispenser 100 unless actuated to do so. This balancealso depends at least on the tube dimensions such as the size of thedroplet emitting outlet orifice.

In some embodiments, the dispenser 100 is also utilized to aspirate oracquire liquid directly from a source 20 (e.g., vial, microtiter ormicro-well plate and the like) by dipping the tip of the capillary tubeinto the liquid to be aspirated and applying a vacuum or suction to drawfluid into the tube. This can be done by using a vacuum source, pump 22such as a positive displacement pump or the like. The system 10 can bearranged to accommodate both modes of acquiring the liquid to bedispensed (i.e., from the source 16 or the source 20), for example, byproviding a two-way valve 24 or the like positioned as shown in FIG. 1A.Various other valves or the like may be provided in the system tubing tocontrol fluid communication and flow, as needed or requires, withefficacy.

The liquids involved can include a wide variety wherein micro-volumes offluid are to be handled, transferred and dispensed. These include, butnot limited to, are liquids such as chemical and biological reagents,for example, DNA, cDNA, RNA, proteins, peptides, oligonucletides,chromosomal formulations, and other organic or inorganic compounds,among others, or the like as known in the art.

The target or substrate 14 can comprise, for example, but not limitedto, a microtiter or micro-well plate, glass slide, receptive membrane,test strip, vial or other suitable target, among others, or the like asknown in the art.

Relative motion between the various components of the system 10 can beprovided to accurately place, position and move them relative to oneanother. An X-, X-Y or X-Y-Z motion system 26 can be used to move theone or more dispensers 100 relative to the one or more targets orsubstrates 14, and/or the fluid or liquid sources 16 and 20 to providethe desired accuracy in dispensing and aspirating. For example, one ormore suitable robot or robotic arms may be efficaciously used, as neededor desired, to provide the controlled relative motion

The one or more targets or substrates 14 can be mounted on a carrierplatform, table or carriage 28 to provide X-, X-Y or X-Y-Z motion. Robotor robotic arms may be utilized with efficacy, as required or desired.Similarly, relative motion of the fluid or liquid sources 16 and 20 canbe controlled in a coordinated manner to allow for efficient liquidtransfer. Web, reel or conveyor belt transport mechanisms can beefficaciously utilized to move any of the fluid targets or sources, asneeded or desired.

In some embodiments, a droplet imaging system 30 is provided to analyzeand visualize the dispensed droplet characteristics. These include, butare not limited to, the droplet volume, shape, sphericity, velocity,among others. This is not only useful during operation of the liquidhandling system 10 but also initial system set-up for a particularapplication. For example, the imaging system 30 can be employed so thatthe various system operational parameters are fine tuned to the specificapplication. These parameters can then be adjusted to provide dropletshaving the required or desired properties.

The imaging system 30 can visualize and analyze droplets in flight. And,as such, cab adjust certain parameters, such as, but not limited to the,piezo-actuating voltage pulse profile, magnitude or frequency, and thelike

In one embodiment, the imaging system 30 comprises a high speed videoinstrument model JetExpert manufactured by ImageXpert Inc., Nashua,N.H., U.S.A. which is used to analyze and visualize dropletcharacteristics or properties such droplet size, droplet velocity, amongothers.

The liquid handling system further comprises a control system orcontroller 32 to monitor and control system operation. Suitable software34 is utilized for users to control the various system parameters andoperations. The controller 32 can include or be interfaced with varioussub-controllers, such as, the piezoelectric dispenser 100, control andelectronics circuitry or module 36, and those of the various motion,imaging and fluid flow and dynamic systems, among others, as needed ordesired, with efficacy. The electronics module or energy source 36provides a pulsed voltage signal 38 to actuate the piezoelectricdispenser 100.

It is preferable to fine tune the pulsed voltage signal 38 such that itis not strictly in a square or rectangular format to avoid sudden impactwith the dispensing tube, but rather such that it is adapted todesirably comprise smooth signal transitions. This can advantageouslyresult in improved droplet structure, droplet volume control and thelike. The electronics module or energy source 36 can be configured withan arrangement of resistors, capacitors and the like to ensure creationof such a preferred voltage signal 38. The smooth transition can be moreadvantageous when relatively larger droplets are to be dispensed.

Though FIG. 1A shows only a single dispenser 100, in other embodiments,it is contemplated that multiple dispensers in linear (1×N) ortwo-dimensional (M×N) arrays are used. These may be provided andoperated either in parallel or in another coordinated fashion, asdesired. It should be understood that any discussion herein withspecific reference to the single dispenser embodiment is substantiallyequally applicable, with possible modifications as apparent to theskilled artisan, to multiple dispensers actuated by one or morepiezoelectric actuators or transducers. In addition, fluid may beprovided to multiple dispensers using a manifold configuration, asneeded or desired. Moreover, the system 10 can be configured to provideon-the-fly dispensing of liquid droplets 12 as deemed suitable. Forexample, as disclosed in U.S. Pat. No. 6,063,339, the entirety of whichis hereby incorporated by reference herein.

FIG. 1B illustrates a longitudinal transducer or transmission 40 inaccordance with some embodiments. The longitudinal transducer 40generally comprises a piezoelectric actuator or device 126 operativelycoupled to a tube 114. The linear or longitudinal piezoelectric actuator126 can be clamped to the tube 114, as discussed further below andherein.

The longitudinal transducer 40 can further comprise a preloading,clamping, retaining or biasing screw, mechanism, device, assembly orstructure 128, 176 that allows for the tube 114 and piezoelectricactuator 126 to be separated, as discussed further below and herein.Optionally, the piezoelectric actuator 126 can be fixedly attached(e.g., bonded) to the tube 114 and the preloading device may be replacedby a fixedly attached support structure or the like to provide areactive force to the force generated by the piezoelectric actuator 126.The piezoelectric actuator 126 can be on a portion or side of the tube114 with the preloading device 128, 176 or support structure being on agenerally opposed portion or side of the tube 114. Optionally, thepiezoelectric actuator 126 can substantially completely surround,encircle or circumscribe the outer periphery of the tube 114. A sleeve,pad or the like may be provided intermediate the piezoelectric actuator126 and the tube 114. Similarly, a sleeve, pad or the like may beprovided intermediate the preloading device 128, 176 (or supportstructure) and the tube 114.

In operation, a voltage pulse (or alternating voltage) actuates thepiezoelectric actuator 126 so that it expands and a generally radialforce 52 is exerted or applied on the wall of the tube 114 at generallyregion 54 of the tube. The region 54 is spaced by a predetermineddistance from a distal tip 42 of the tube 114. This radial force 152causes a small deformation 46 and radial motion, displacement ormovement 48 of the tube 114. Further, acoustic pressure or stresspropagates or is transmitted axially or longitudinally from the regionor area 54 of the tube 114, through the wall of the tube 114 and towardthe tube tip 42 which undergoes distal axial or longitudinal motion,displacement or movement 50 in a direction extending away from thepiezoelectric actuator 126 (motion in a distal, or negative or −Zdirection). Thus, a stress or pressure wave 44 passes longitudinally oraxially through the tube wall and provides for transmission orconversion of tube radial motion 48 to axial or longitudinal motion 50at the tube tip 42. In some embodiments, the wave 44 has a generallysinusoidal or cosine waveform, profile or configuration.

On completion of one cycle, the tube 114 reverts back to its deactivatedstate with radially outward tube motion 48 and proximally retractingtube tip axial motion 50 in a direction extending toward thepiezoelectric actuator 126 (motion in a proximal, or in a positive or +Zdirection). When multiple pulses of an alternating voltage causeexpansion and contraction of the piezoelectric actuator 126 the tube tip42 undergoes multiple axial or longitudinal oscillations 50.

It should be appreciated, that various embodiments contemplate andutilize the balance between the voltage pulse (or alternating voltage),the configurations, arrangements, sizes and/or dimensions of thepiezoelectric actuator 126 and tube 114 to provide a stress or pressureprofile and wave form that results in a controlled and/or predeterminedaxial displacement or oscillation at the distal tip 42 of the tube 114.

The longitudinal transducer 40 may be utilized with any of theembodiments of the dispensers disclosed or suggested herein. Thesedispensers would generally comprise the longitudinal transducer 40 incombination with a liquid to be dispensed in the tube 114 and possibly asuitable nozzle or aperture plate to define an aperture or outletorifice at the tube's distal tip 42. Thus, in operation, the dispenserscan provide for droplet dispensing (such as drop-on-demand dispensing)wherein the tube tip longitudinal or axial oscillation or motion createsa suitable solid-liquid dynamic interaction to facilitate ejection ofsingle droplets of a predetermined size.

Embodiments of the longitudinal transducers and/or dispensers disclosedherein can be thought of as providing q unique ultrasonic horn whereinthe transmission of longitudinal acoustic waves is utilized to transmitand/or convert radial tube motion to controlled and predetermined axialmotion of the tube.

FIGS. 2 to 4 illustrate different views and/or arrangements of apiezoelectric dispensing device or dispenser 100 for fluid handling andtransfer in accordance with some embodiments, with like referencenumerals corresponding to like elements or structures. The dispenser 100generally comprises, for illustrative purposes two assemblies, orsub-assemblies 110 and 112.

The first structure, arrangement, assembly or sub-assembly 110 (boundedby dashed lines, merely for illustrative purposes, in FIG. 2) comprisesa capillary tube 114 and a dispensing nozzle 116 generally including anaperture or outlet orifice structure or plate 118. However, these arenon-limiting descriptions such that the outlet 118 and nozzle 116 can bepart of or incorporated into the tube 114 or assembly 110.

The second structure, arrangement, assembly or sub-assembly 112 can beviewed as, for example, but not limited to, a piezoelectric C-Clampsub-assembly or the like that comprises a mount, support structure orbracket 120. The bracket 120 comprises a couple of opposed jaws or arms122 and 124. A piezoelectric actuator, transducer, element, stack orassembly 126 is mounted on the first arm 122 and a preloading, clamping,retaining or biasing screw, mechanism, device, assembly or structure 128is mounted on the second arm 124.

FIG. 3 illustrates the dispensing device or dispenser 100 in a preloadedor clamped position. The screw 128 is fastened and locks the capillarytube 114 in place by applying force in the radial direction of the tube114 such that tube 114 is retained between the piezoelectric actuator,transducer or element 126 and the screw 128. (Further structural detailsof the preloading clamping jaws are discussed below with particularreference to FIG. 4, and show that in accordance with some embodimentsrespective opposing portions of respective jaws are positionedintermediate the piezoelectric element, the screw and the tube.)

The dispenser 100, in some embodiments, includes or incorporates thelongitudinal transducer 40. This longitudinal transducer 140 cangenerally comprise the tube 114, piezoelectric actuator 126 and theclamping or preloading device 128. The piezoelectric actuator 126 can bea linear or longitudinal piezoelectric actuator 126 clamped to the tube114.

Upon actuation of the piezoelectric actuator, transducer or element 126,such as by a voltage pulse or an alternating voltage, it expands and apulse of force 52 is applied in a generally radial direction 130 towardthe tube 114. The force 52 produces stress in the tube wall at theclamped preloaded region 132 of the tube 114. Stress or pressure in theregion 132 produces an acoustic pressure or stress wave that propagatesor is transmitted longitudinally through the wall of the tube 114 towardthe nozzle aperture plate 118 and distal tip 42. This involvestransmission or conversion of the radial inward motion to be transmittedin a form that results in a distally extending axial or longitudinalmotion or displacement 50. This dynamic interaction between the solidwall of the tube 114 with the liquid at the aperture 136 causes anejection of a droplet 12 of a predetermined size from the aperture 136.Stated differently, or in other words, or explained differently,transmission of acoustic pressure to the fluid or liquid in the regionof the aperture plate 118, is at least partially responsible, for thepropulsion or ejection of droplets 12 of fluid or liquid 134 through theaperture or outlet orifice 136.

Thus, the pressure or stress wave passing longitudinally through thetube wall provides a unique axial displacement of the distal tube tip42, aperture plate 118 and/or aperture 136 for dispensing of singledroplets 12. In some embodiments, this wave has a generally sinusoidalor cosine waveform, profile or configuration. After application of eachpulse, the piezoelectric actuator, transducer or element 126 radiallyexpands and axially contracts back to its original size therebyinvolving an oscillation or oscillatory motion of the tube tip 42.

The fluid or liquid 134 level 103 in the tube 114 may be at any pointabove or below the clamping area 132. With respect to the liquid level103 being below the clamping area 132 and/or the piezoelectric actuator,provides a major advantage over conventional piezoelectric dispensingtechnology, wherein the liquid level has to be at least at the level ofthe piezoelectric or higher. Again, this translates into the advantagesof the unique features of at least the longitudinal transducer 140wherein transmission or conversion of radial motion to axial motionprovides a new dimension of control for accurately dispensingpredetermined quantities of fluid in the form of single droplets from adistal tip of the dispenser.

Desirably, in accordance with some embodiments, prior to dropletejection, the balance between the hydrostatic pressure head, surfacetension and capillary forces maintains the liquid 134 within the lumenof the tube 114 and substantially no liquid is adhesively suspended fromthe aperture or outlet orifice 136. The hydrostatic pressure head can becontrolled, as needed or desired. (Optionally, the tube 114 can be opento the atmosphere or ambient conditions, as needed or desired.)

Accordingly, following each use the tube 114 may be removed and replacedby releasing preloading screw 128. The tube 114 may be disposedfollowing each use, such as with a particular liquid, thereforeeliminating the need for cleaning and the risk of contamination frommaterial left over from a prior use.

In some embodiments, the tube 114 comprises glass. In some embodiments,the tube 114 comprises another rigid material that has a predeterminedor preselected modulus of elasticity. In one embodiment, the materialforming the tube 114 has a modulus of elasticity greater than about 10GPa. In one embodiment, the material forming the tube 114 has a moduleof elasticity greater than about 50 GPa. A higher module of elasticityproduces higher stress in the tube wall since the stress is a product ofthe elasticity and the deformation. This higher stress desirably resultsin a higher amplitude of oscillation of the capillary tube 114.

The capillary tube assembly 110 can comprise a sleeve 138 or the likethat substantially surrounds or circumscribes the tube 114. The sleeve138 desirably distributes the force imposed by the piezoelectricactuator, transducer or element 126 and prevents stress concentrationlocally or in one spot which may cause breakage of the tube 114, such asone made of glass, other rigid material or the like.

The sleeve 138 can comprise a variety of suitable materials. In oneembodiment, the sleeve 138 is made of a metal or alloy such as stainlesssteel, brass or aluminum, or the like, among others. In anotherembodiment, the sleeve 138 is made of a plastic such as Delrin®, or thelike, among others.

The sleeve 138 is bonded to the capillary tube 114 by a structural epoxysuch as, but not limited to, LOCTITE® Hysol® type E-30CL. Thus, thecapillary tube assembly 110 comprising the tube 114 and the sleeve 138is separable from the dispenser 100 and disposable.

The aperture plate 118 can, in some embodiments, be bonded to the tube114 and can be manufactured by electroforming. In one embodiment, thenozzle aperture plate 118 comprises or is made of electroformed nickelor electroformed palladium nickel.

Optionally, the aperture plate 118 may be plated by inert material suchas titanium nitride or the like with efficacy, as needed or desired. Inone embodiment, the aperture plate 118 comprises synthetic sapphire,ruby or the like. The aperture plate 118 may be gold plated. In oneembodiment, the thickness of the aperture plate 118 can be in the rangeof about 60 microns (μm), though higher or lower thicknesses may beefficaciously utilized, as required or desired.

As shown in the drawings, in some embodiments, the aperture plate 118has a funnel-like, conical, frusto-conical structure or the like with acurvature that defines a first larger size or diameter at an upstreamend and a second smaller size or diameter at a downstream end, that is,at the aperture or outlet orifice 136. Advantageously, such aconfiguration can provide improved consistency in control of the dropletsize and mitigation of “dead” fluid spots or regions. Moreover, thisdesirably results in improved overall system operation.

The piezoelectric or piezoceramic actuator, transducer or element 126can comprise a co-fired monolithic linear or longitudinal stack whichexpands and contracts, generally linearly or longitudinally in thedirection of the stack, under the input of an alternating voltage. Inone embodiment, the piezoelectric or piezoceramic actuator, transduceror element 126 is manufactured by NEC part No. AE0203D04Fas sold byTHORLAB. Inc, Newton, N.J., U.S.A.

The clamping or preloading force of the piezoelectric actuator 126 canbe varied based on the input voltage signal as well as the configurationof the piezoelectric device itself. In one embodiment, the maximumclamping force of the actuator 126 is in the range of about 200 Newton,though clamping forces below about 2 Newton and above about 250 Newtonmay be efficaciously utilized, as required or desired.

The clamping or preloading force of the clamping screw 128 can be variedbased on the device and screw configuration. In one embodiment, theclamping screw 128 provides a preloading or clamping force of in therange from about 30 Newton to about70 Newton, including all valued andsub-ranges therebetween, though higher or lower forces may be provided,as needed or desired. The screw 128 can be locked using a torquelimiting screw driver which limits the linear force to a predeterminedvalue, such as, but not limited to 70 Newton.

As discussed above with particular reference to FIG. 1A, the dispenser100 may be used to acquire fluid or liquid samples as well as dispensefluid or liquid droplets. Acquiring samples is done by submerging thecapillary tube 114 in a fluid sample and applying vacuum, suction or thelike.

Capillary tube 114 has a generally tubular axis-symmetric shape with agenerally thin wall having a thickness T as labeled in FIG. 2. In oneembodiment, the thickness T is in the range from about 0.1 mm to about0.5 mm, including all values and sub-ranges therebetween. In oneembodiment, the length of the capillary tube 114 is about 25 mm and thedistance of the tube aperture from the clamping point, location orregion is desirably greater than about 13 mm such that the capillarytube can be conveniently submerged in a standard laboratory 10 mm deepwell plate. Of course, these dimensions can be efficaciously modified toaccommodate differently configured well plates, micro-titer plates andthe like, among others, as required or desired.

In another embodiment, the thickness T is in the range from about 0.1 mmto about 0.3 mm, including all values and sub-ranges therebetween. Ofcourse, higher or lower tube wall thicknesses may be provided withefficacy, as needed or desired. Advantageously, in accordance withcertain embodiments, the generally thin wall structure of the capillarytube 114 allows for the piezo-induced stress to be substantiallytransmitted to the tube wall in a longitudinal manner as opposed to intothe liquid therein, thereby providing additional control on the dropletejection and the goal of achieving droplet sizes in the low picoliterrange. Moreover, the relatively thin tube wall allows for a lowpiezoelectric force to be applied thereat such that the low forcecreates a sufficiently high tube wall stress or pressure with a lowradial tube bending and a controlled axial tube displacement oroscillation, while minimizing transmission of compressionpressure/stress to the liquid in the tube at the region of applicationof the radial force.

Typically, the tube 114 and its lumen have a generally circularcross-section. However, the cross-section of the tube 114 and its lumenmay have other shapes, such as, but not limited to square or hexagonalcross sectional shapes.

In one embodiment, the tube 114 may have two unequal outer diameters ateach end labeled D1 and D2 in FIG. 2 with D2 being greater than D1. Inanother embodiment, the tube 114 may have an even diameter through itslength. Diameter D1 may be in the range from about 1 mm to about 5 mmand diameter D2 is generally smaller than about 9 mm Of course, largeror smaller diameters may be provided with efficacy, as needed ordesired. In some embodiments, larger opening or diameter D2 may be usedfor storage of fluid or liquid sample, such as DNA samples, as discussedfurther below.

In one embodiment, a pulsating electrical signal at a frequency in therange from about 10 Kilohertz (KHz) to about 100 KHz is provided to thepiezoelectric or piezoceramic actuator, transducer or element 126 toproduce ejection of single droplets from the produces ejection ofdroplets 12 from the nozzle aperture plate 118. In other embodiments,higher or lower frequencies may be utilized with efficacy, as needed ordesired.

The time of actuation (or expansion) of the piezoelectric orpiezoceramic actuator, transducer or element 126 depends on variousfactors, such as, but not limited to, the system or deviceconfiguration, dimensioning and droplet size. In some embodiments, thistime is of the order of a microsecond (μsecond) up to about in the rangeof tens or hundreds of microseconds (μseconds), as required or desired.Of course, higher or lower actuation times may be utilized withefficacy.

Typically, a single oscillation cycle ejects a single droplet 12 whichhas a droplet diameter that is substantially equal to the diameter ofthe aperture or outlet orifice 136. Thus for example, a 50 micron (w)aperture size or diameter produces a droplet with a diameter of about 50microns (w) and having a volume of about 65 picoliters (pL). Similarly,an aperture of 70 μm produces a droplet with a volume of about 180 pL.

Fluids or liquids can be dispensed one droplet or drop at a time in a“drop-on-demand” mode at frequencies up to and in the range of about1,000 drops per second. The dispensing device or dispenser 10) may beused in the production of arrays, such as DNA microarrays and the like,and multiple assays. The placement of the droplets 12 on a target orsubstrate can be controlled, for example, by a programmable positioningtable which may move along the three axis (X, Y and/or Z) of a Cartesianor equivalent coordinate system, as discussed above and with particularreference to FIG. 1A.

FIG. 4A illustrates a more detailed top view of the clamping area of thetube 114 and engaging structural portions 142 and 144 of respective jawsor arms 122, 124. This drawing also shows the tube 114, thepiezoelectric device 126, the clamping screw 128, and the sleeve 138. Inone embodiment and as illustrated, the clamping jaw portions 142 and 144have a generally V shape and which have four interface points P1, P2, P3and P4 with the sleeve 138. This configuration can advantageouslycontribute to and enhance a generally balanced and even distribution ofthe stress in the clamped region of the tube 114.

The angle of the “V” shape may be efficaciously varied such that it canbe greater or less than a right-angle (90 degrees) configuration. Thenumber of interface points may also be varied, as needed or desired.

Clamping jaw portions 142 and 144 may optionally have a curved, arced orarcuate shape with a radius of curvature that is equal to or greaterthan the radius of (curvature) of the sleeve 138. Of course, otherconfigurations may be practiced in accordance with embodimentsdisclosed, taught or suggested herein. Arrows 146 and 148 schematicallydepict the clamping, preloading and/or piezo actuation forces.

FIG. 4B illustrates a detailed top view of an alternative configurationof the V shaped coupling that is shown in FIG. 4A. The capillary tube114 b is shown clamped between a front V block 142 b and a rear V block144 b. The piezoelectric actuator 126 b is coupled to the rear V block144 b. A mounting block 312 is shown connected to the piezoelectricactuator 126 b. The mounting block 312 may serve as a heatsink in someembodiments. Electrical leads 314 are illustrated entering the mountingblock 312.

FIG. 5A illustrates an arrangement of a piezoelectric dispensing deviceor dispenser 100 a for fluid handling and transfer in accordance withsome embodiments, with like reference numerals corresponding to likeelements or structures, which utilize a capillary tube 114 with agenerally annular gap 152. This annular gap 152 is provided between thetube 114 and a concentric core member 150 which would typically have,but not limited to, a cylindrical structure.

Many configurations and sizes of the gap 152 can be contemplated inaccordance with embodiments of the dispenser 100 a. For example, if theinternal diameter of the tube 114 is about 1 mm, then the outer diameterof the core member 150 can be about 0.9 mm, thereby providing a radialgap of about 0.05 mm between the tube 114 and the core member 150 whichdefines the size of the annular capillary gap. One advantage of such anannular gap 152 configuration is that it can assist in reducing thehydrostatic pressure head that acts against or on the nozzle apertureplate 118 and/or the aperture or orifice outlet 136 relative to thecapillary forces and surface tension involved. Desirably, this canresult in more consistency, accuracy and reliability in dispensing of aparticular or predetermined droplet size.

Moreover, the piezoelectric dispenser 100 a further distinguishes overconventional devices which employ acoustic pressure wave propagationthrough the liquid for droplet dispensing. The droplet dispensingoperation of the dispenser 100 a is substantially independent of how theliquid 134 is loaded within the tube 114. At least one reason for thisis that a longitudinal transducer 140 is utilized which converts radialtube motion to axial tube displacement at the distal tube tip 42 and/orthe dynamic interaction between the solid wall of the tube 114 with theliquid at the aperture 136.

FIG. 5B is a simplified schematic side view of a piezoelectric fluiddispenser incorporating a tube showing another configuration of thedispenser shown in FIG. 5A. A top view of this same configuration isillustrated in FIG. 4B. In addition to the previously describedcomponents and features, the side view also shows the fluid column 134 band the capillary aperture 136 b.

FIG. 6A illustrates an arrangement of a piezoelectric dispensing deviceor dispenser 100 b for fluid handling and transfer in accordance withsome embodiments, with like reference numerals corresponding to likeelements or structures, which utilize a main body portion or bracket 154and that can be particularly advantageous in dispensing of fluids orliquids suitable for in production of dot arrays or assays, among otherapplications as disclosed, taught or suggested herein.

The dispensing device or dispenser 100 b generally comprises a capillarytube assembly 110 that includes a tube 114 and a piezoelectric clampassembly 112. The tube 114 includes a dispensing nozzle 116 generallydefined by an aperture plate 118. The clamp assembly 112 can include amounting bracket 120 that can be part of the main body portion 154 orincorporated therein. The bracket 120 has a first jaw or arm 122 thatincludes the piezoelectric or piezoceramic actuator, transducer orelement 126 while a second jaw or arm 124 includes the preloadingmechanism or screw 128. The screw 128 preloads the tube 114 against thepiezoelectric device 126 such that the tube is desirably locked orfixtured in place between the piezoelectric device 126 and the screw 128in a manner as is described herein. The main body portion 154 can havevarious structural features that allow for the assembly of thedispensing system including, but not limited to, connection, attachmentand coupling devices or the like, among others.

As taught herein, the piezoelectric device 126 expands and contracts inthe direction 130 in response to an alternating electrical voltagewhich, in accordance with certain embodiments, can be in the range ofabout 50 volts (such as in the range from, but not limited to, about 59or less to about 62 or more volts) at a frequency of about 30,000 Hertz(Hz). This displacement of the piezoelectric actuator, transducer orelement 126 produces one or more pulses of force in the radial direction130 toward the tube 114. This force produces stress in the clampingregion 132 of the capillary tube 114. This stress generates a wave whichpropagates longitudinally through the tube wall toward the nozzleaperture plate 118 wherein transmission of acoustic pressure to thefluid or liquid 134 in the region of the aperture plate 118 (viasolid-fluid/liquid interaction) propels a droplet 12 of fluid throughthe aperture or outlet orifice 136. As also discussed above and herein,the stress/pressure wave passing longitudinally through the tube wallprovides a unique oscillating distal tube tip 42, aperture plate 118and/or aperture 136. In some embodiments, this wave has a generallysinusoidal or cosine waveform, profile or configuration.

FIG. 6B is a simplified schematic side view of a piezoelectric fluiddispenser incorporating a mounting bracket suitable for dispensing offluid in the production of dot arrays or the like illustrating anotherconfiguration of the dispenser shown in FIG. 6A. A top view of this sameconfiguration is illustrated in FIG. 4B. In addition to the previouslydescribed components and features, the side view in FIG. 6B also showsthe adjustment screw 128 b.

FIG. 7 illustrates an arrangement of a piezoelectric dispensing deviceor dispenser 100 d for fluid handling and transfer in accordance withsome embodiments, with like reference numerals corresponding to likeelements or structures, which include a plurality or multiplicity ofpiezoelectric clamps or assemblies, such as 112′ and 112″. The dispenseror dispensing device 100 d and/or the respective assemblies 112′ and112″ generally comprise two sets of piezoelectric clamps, elements,transducers or elements 126′, 126″ which are operatively coupled torespective two preloading clamping screws 128′, 128″. A bracket or mainbody portion 120′ comprises part of the device.

The piezoelectric dispensing device or dispenser 100 d includes the tube114 which is closed at one end 168 and forms a shape of a vial (e.g.,comprising glass) which can be used for storage of fluid or liquidsamples.

In some embodiments, the screw 126′ can be provided with a resilientmember such as a spring 170, for example, a torsion spring or the like.The torsion spring 170 can be biased in a clockwise direction, oralternatively a counter-clockwise direction, to apply a substantiallyconstant torque on the screw 112′ such that the radial (or axial ifviewed relative to a X-Y-Z Cartesian coordinate system)/force 172applied by the screw 128′ remains substantially constant duringoperation of the dispensing device or dispenser 100 d.

Advantageously, the torsion spring 170 can prevent accidental damagewhich may be caused by manually over tightening of the screw 128″. Inone embodiment, but not limited to, an M5-0.8 screw may be used inconjunction with the torsion spring 170 to apply a predetermined torque,for example, of about 0.03 Nm in a clockwise direction to produce aradial/linear force 172 of about 70 Newton.

FIGS. 8-11 illustrate different views and/or arrangements of apiezoelectric dispensing device or dispenser 100 e for fluid handlingand transfer in accordance with some embodiments. The dispenser 100 egenerally comprises a main body portion or bracket 174, a capillary tube114, a piezoelectric actuator, transducer or element 126, and apreloading, clamping, retaining or biasing mechanism, device, assemblyor structure 176 that can clamp the linear or longitudinal piezoelectricactuator 126 to the tube 114.

FIG. 8A is a simplified perspective view of a piezoelectric fluiddispenser incorporating a spring biased preloading mechanismillustrating features and advantages in accordance with certainembodiments.

FIG. 8B is a simplified perspective view of a piezoelectric fluiddispenser illustrating an alternative configuration of the dispenser inFIG. 8A. The fluid dispenser in this embodiment includes in addition tothe previously described components and features, a dispense headmounting screw 316, as well as an electrical connector 318.

The dispenser 100 e further comprises a connector sleeve 178 that iscoupled to or engaged with a pin 180 or the like which in turn iscoupled to or engaged with one end of the piezoelectric actuator,transducer or element 126. The other end of the piezoelectric actuator,transducer or element 126 is coupled to or engaged with a pad or sleeve182 or the like which in turn is coupled to or engaged with the tube114. The pad or sleeve 182 can be bonded to the tube 114 and incombination advantageously provides for a replaceable, removable anddisposable unit.

The main body portion or bracket 174 houses and/or supports the variousdispenser components. Various clearance spaces and openings can beprovided to allow for positioning of the components and passage of wiresor cables and the like. The pad or sleeve 182 can be formed by variousmethods, such as, but not limited to, electrical discharge machining(EDM).

The preloading, clamping, retaining or biasing mechanism, device,assembly or structure 176 generally comprises a spring 184, such as aleaf spring coupled to a mass ball 186 and an actuation arm or lever 188to provide preloading or clamping on a portion of the tube 114 that isopposed to the piezoelectric actuator, transducer or element 126. Theradial forces are shown in FIG. 13 as arrows 190 and 192. The motion ofthe arm or lever 188 in directions 194 causes the leaf spring to applyand release a force on the mass ball 186 which in turn selectivelyapplies a force on the clamped region 196 of the tube 114. Desirably,the mass ball 186 provides a reactive opposing force in response to theactuation force of the piezoelectric actuator, transducer or element126. The mass ball 186 may comprise a magnet for coupling with, forexample, the leaf spring 184, such that in some embodiments it wouldprovide clearance space for removal and replacement of the dispensingcapillary tube 114.

The preloading, clamping, retaining or biasing mechanism, device,assembly or structure 176 of the dispenser 100 e can be efficaciouslyemployed with any of the dispensing systems and devices disclosed,taught or suggested herein. The operation of the piezoelectric actuator,transducer or element 126 of the dispenser 100 e is similar to asdescribed above and herein.

FIG. 9A is a simplified exploded perspective view of the piezoelectricfluid dispenser of FIG. 8A illustrating features and advantages inaccordance with certain embodiments.

FIG. 9B is a simplified exploded perspective view of the piezoelectricfluid dispenser of FIG. 8B, illustrating features and advantages of thatalternative configuration. In addition to the previously describedcomponents and features, the illustrated exploded view also shows theconnector housing 320.

It should be noted that, in accordance with embodiments of thepiezoelectric dispenser disclosed herein, the piezoelectric device 126does not completely surround, encircle or circumscribe the outerperiphery of the dispensing tube 114, but does so only partially. Statedotherwise, the piezoelectric device is on a first side of the tube whilethe preloading device is on a second substantially opposed second sideof the tube. In any of the embodiments disclosed herein, thepiezoelectric device can comprise a linear or longitudinal transducer126 that is clamped to the capillary tube 114.

FIG. 11A is a simplified sectional side view of the piezoelectric fluiddispenser of FIG. 8A illustrating features and advantages in accordancewith certain embodiments.

FIG. 11B is a simplified sectional side view of the piezoelectric fluiddispenser of FIG. 8B, illustrating features and advantages of thatalternative configuration. In addition to the previously describedcomponents and features, the illustrated sectional side view also showsthe connector housing mounting screw 321.

The systems, devices, methods and techniques disclosed or suggestedherein have various industrial applications. These may be used fordispensing and aspiration of any fluid, which has a viscosity, but notlimited to, in the range of about 1 cps to about 30 cps, including allranges and sub-ranges therebetween. The nozzle aperture plate may haveone aperture or a plurality or multiplicity of apertures or outletorifices.

The size or diameter of the aperture or outlet orifice may be in therange from about 5 microns (w) or less to about 150 microns (w) or more.In some embodiments, apertures or outlet orifices that have a size ordiameter in the range from about 5 microns (w) to about 10 microns (w)can generally produces fine droplets which may be used in the productionof a wide variety of aerosol and sprays of various chemical, biologicalor pharmaceutical materials and liquids.

In one embodiment, the dispensing device or dispenser as disclosedherein may be used as a hand held writing instrument such as an airbrush instrument. In this embodiment, the tube may be filled with ink,coloring fluid(s), liquid(s) or the like. In another embodiment, thedispensing tube may comprise a hypodermic needle for delivery of localanesthetic into inflated abdominal space prior to or during alaparoscopy surgical procedure.

FIGS. 12-14 show different views and/or arrangements of a capillary tubeassembly 214, in accordance with some embodiments, which can be used inconjunction of any of the dispensing devices or dispensers disclosedherein. In general, such a configuration allows a flexible coupling forthe capillary assembly, which advantageously compensates for anyundesirable upstream movement caused in the fluid inlet line to allowfor proper piezo alignment and operation, while not disturbing theaccurate dispensing of fluid from the capillary tube. Advantageously,this also provides for a self-aligning feature and coupling between thecapillary tube and the fluid inlet line.

One example of an issue to be addressed is in the capillary design andits connection to the external fluid, liquid or reagent supply line. Thecapillary tube, in accordance with some embodiments, comprises anelongated glass tube which has two ends. The first upper end defines afluid inlet to the capillary tube and the lower end defines a dropletdispensing outlet. The lower end is provided with an aperture platewhich controls, along with other factors, the size of the droplet to bedispensed.

When the capillary tube receives a piezo-generated radial pulse bothends produce longitudinal displacement pulse. The lower aperture endgenerates the droplet ejection as expected but the displacement at theupper end can in some cases be a problem particularly if the capillarytube is tightly constrained at the upper upstream end.

Probably because there is reaction force which shakes the capillary tubeand affects the droplet formation and/or accuracy. In some cases, thetrajectory of the droplet could be affected and in some other casesmultiply drops may be generated, which embodiments provide solutionsfor.

For instance, it has been noted that if the inlet end of the capillarytube is lightly or loosely supported then the noted disturbance problemis substantially reduced or disappears.

Accordingly, in accordance with some embodiments, an upstream orproximal fluid inlet or supply line is connected to the capillary tubeusing a generally small diameter flexible thin-wall polypropylene (PP)tube. The capillary tube 114, in some embodiments, is connected to thisintermediate fluid supplying tube through its internal diameter. Inaddition, and in accordance with some embodiments, this intermediatesupply tube desirably also has a substantially low bending stiffnesswhich allows the capillary tube 114 to easily align to the V groove atthe piezo head (see, for example, the embodiment of FIGS. 4A and 4B andrelated description).

FIG. 12A is a simplified exploded perspective view of a capillary tubeassembly of a piezoelectric fluid dispenser illustrating features andadvantages in accordance with certain embodiments.

FIG. 12B is a simplified exploded perspective view of a capillary tubeassembly of a piezoelectric fluid dispenser illustrating an alternativeconfiguration from that shown in FIG. 12A. In addition to the previouslydescribed components and features, this exploded view of the capillarytube assembly also shows a capillary fluid inlet connector 324 and acapillary tube mounting nut 322.

FIG. 13A is a simplified front or rear planar view of the capillary tubeassembly of FIG. 12A illustrating features and advantages in accordancewith certain embodiments.

FIG. 13B is a simplified front or rear planar view of the capillary tubeassembly of FIG. 12B illustrating features of that alternativeconfiguration. In addition to the previously described components andfeatures, this

FIG. 14A is a simplified sectional view of FIG. 13A illustratingfeatures and advantages in accordance with certain embodiments.

FIG. 14B is a simplified sectional view of FIG. 13B illustratingfeatures of that alternative configuration.

In accordance with some embodiments, the capillary tube assembly 214generally comprises the distal capillary tube 114, an intermediatesupply line connection tube 216, a proximal intermediate supply lineconnection tube 218, and a fluid inlet port 220 that receives flow 222of the fluid to be dispensed. O-rings 250 or the like can provide forsealing coupling between selected components of the assembly 214.

In some embodiments, the capillary tube assembly 214 further comprises acapillary protective cover 260 and a capillary housing 270. In onenon-limiting embodiment, the capillary housing 270 comprises a plasticor thermoplastic such as polyether ether ketone (PEEK).

In one non-limiting embodiment, the capillary tube 114 comprises glassand has an outer diameter of about 1.5 mm and an inner diameter of about800 microns (μm) or less. In one non-limiting embodiment, the fluidsupply connection tube 216 comprises polypropylene and has an outerdiameter of about 800 μm and an inner diameter of about 500 μm or less.In one non-limiting embodiment, the fluid supply connection tube 218comprises PEEK plastic and has an outer diameter of about 1.5 mm and aninner diameter of about 800 μm or less.

The fluid supply line 216 that connects or couples to the capillary tube114 desirably has a relatively small inner diameter. In onenon-limiting, the inner diameter of the fluid supply line or connectiontube 216 is about 500 μm or less. In another non-limiting, the innerdiameter of the fluid supply line or connection tube 216 is about 250μm.

In one non-limiting embodiment, the supply lines, such as the connectiontubes 216 and 218, are made from PEEK and/or polypropylene plastic orthermoplastic. The small tube diameter and the surface energy of theplastic, such as PEEK, desirably produce a capillary force that holdsthe fluid tightly within the supply lines. In this way, andadvantageously, the movement of the system's X-Y-Z table is minimallytransferred to the fluid inside the capillary tube 114. This fluidsupply line arrangement desirably also help in generating a consistentdrop size.

The consistency of drop size may be measured by the coefficient ofvariation (CV) using an automatic video inspection system, such as theimaging system 30 (see FIG. 1). The dispensing system or machine isprovided with a vision system which measures the drop size andautomatically calculates and displays real time statistical informationfor the drop size which includes the calculated CV value. Advantageouslythe X-Y or X-Y-Z table is provided with a multiple or 5 phase steppingmotor which generates smooth and continuous movements, which furthercontributes to the consistency of the droplets.

In some embodiments, when the dispensing systems disclosed herein areused to dispense a solution that contains protein there is a possibilitythat one or more molecules of said protein will bind to one or moresurfaces of the capillary tube's aperture or aperture plate and at leastpartially clog the aperture. Advantageously, to prevent any suchundesirable clogging a suitably coated aperture plate is provided.

To prevent any such clogging, in one non-limiting embodiment, a goldplated electro-formed aperture plate may be used. The gold platedaperture may be coated by Self Assembled Monolayer (SAM) whichchemically binds to gold and creates a single molecular layer whichsubstantially prevents or mitigates protein molecule(s) from binding toit. An example of such a self assembled monolayer material is Poly(ETHYLENE GLYCOL) methyl ether thiol CH3O(CH2CH2O)Nch2ch2SH. Theprocedure for preparation and application of such a self-assembledmonolayer (SAM) on gold is defined in Sigma Aldrich Technical Bulletin#AL-266 which is hereby incorporated by reference herein.

In some embodiments, the container or tube assembly 160 can have atapered tube end such that the inner diameter of the tube end distallydecreases to the opening 162 so as to provide an enhanced connectionand/or fusion with the aperture plate 118 and/or the aperture or outletorifice 134.

In some embodiments, a hydrophilic surface treatment is provided onfluid contacting surfaces of the system, such as those of the capillarytube 114 to enhance solid-liquid coupling. Advantageously, thehydrophilic coating enhances the solid-fluid interaction, that is,substantially prevents or minimizes any slippage of the fluid from theoscillating, vibrating or moving tube aperture so that transmission ofmechanical energy (movement or acceleration) to acoustic pressure iseffectively enhanced or improved.

In some embodiments, a hydrophobic coating is provided on externalsurfaces of the system, such as those of the capillary tube 114, so thatno or minimal fluid adheres to the tube's external aperture sides. Inone non-limiting embodiment, the hydrophobic coating comprisesPolytetrafluoroethylene (PTFE).

In some embodiments, a plurality of dispensing heads, including any astaught, disclosed or suggested herein, are combined into a singlesystem, assembly, combination, arrangement or member to provide fordispensing through a system comprising a plurality of piezo-actuatedcapillary tubes. For example, the system can comprise a plurality of thepiezoelectric dispensing devices or dispensers 100 e of FIGS. 8A and 8B.In some embodiments, this system incorporates a multiple unit dispenserblock to advantageously mitigate any displacement issues with respect tothe proper arrangement of the tubes in at least the X-Y plane. In onenon-limiting embodiment, the dispenser block comprises stainless steelso that the piezo impact does not make the block “ring” due to dampeningof energy. In another non-limiting embodiment, the dispenser blockcomprises a material having a density of at least about 5,000 kg/m³ toabout 8,300 kg/m³ is utilized so that the piezo impact does not make theblock “ring” due to dampening of energy.

In some embodiments, a film or the like with predetermined dampingproperties is provided, for example, between the leaf spring 184 andloading ball 186 of FIGS. 8-11. Advantageously, the film providesdamping to mitigate unwanted spring related contact with the ball.Desirably, the film has properties that allow for maintenance of shapeand/or damping properties over an extended time period. In onenon-limiting embodiment, the film comprises a rubber material, such as,EPDM rubber (ethylene propylene diene monomer (M-class) rubber).

In some embodiments, an optimized drive circuitry including acomputerized software and hardware control system is utilized to finetune and/or optimize dispense operations of any of the dispensingdevices, systems, dispenser heads, dispenser blocks or dispensersdisclosed herein based on particular fluid, liquid or reagentproperties. Such a control system or controller can utilize optimizedconfigurations of resistors (e.g., in parallel), potentiometers, andother electronic circuitry components, as needed or desired.Advantageously, this permits operation of the piezo dispensingembodiments disclosed herein to optimally adapt to the fluid beingdispensed, such as certain oils which can efficaciously be dispensed inaccuracy by modifying certain control parameters of the control system.

In some embodiments, a degasser or the like is provided upstream of thedispensing capillary tube 114 such that the fluid, liquid or reagent issubstantially free of any unwanted gaseous content. An optimized fluidcircuit design is utilized, including head height control, to achieveaccurate operation.

In one non-limiting embodiment, the capillary tube 114 is formed from aglass material, such as, borosilicate glass or the like.

EXAMPLES

A primary focus of the following examples was to evaluate transducerdesign.

I. Configuration:

Borosilicate capillary: Spring/Ball/V clamp

60 um sapphire apertures, nickel plated gold apertures

Reagent: BSA, DNA

Voltage only

Using borosilicate glass capillary tubes with sapphire and plated nickelwith gold over-plating, it was found that for an 60 micron aperature, asingle drop size could be achieved between 100-120 pL with voltageadjustments, and for a 100 micron aperture, a single drop size could beachieved between 180-200 pL (See Table I). These results wereindependent of aperture type. Below and above these volumes thedispensed volumes were in the form of multiple smaller drops. The dropdistribution and single drop volume was measured using a horizontal dropcamera which could image both single and multiple drops as well asmeasure the single drop volume. Using a laser interferometer to measurethe displacement of the aperture attached to the glass capillaryparallel to the capillary length it was determined that there was adisplacement wave form that attenuated with time. This was interpretedto indicate that the piezo element displacement was composed of acontinued waveform with amplitude that dissipated with time. Thus, thesingle piezo pulse resulted in a spring like action of the aperture thatwas producing multiple drop formation, but that there was a small volumerange where a stable single drop could be formed. It was determined thatthe source of the aperture vibration was the low compliance of thespring and ball clamp on the side opposite the piezoelectric element.

TABLE I Aperture Voltage Volume CV  60 um 15 V 110 pL 3.9% 100 um 19 V181 pL 2.3%

II. Configuration:

PEEK capillary: Spring/Ball/V clamp

100 um sapphire apertures

Reagent: BSA, DNA

Voltage only

Using a similar size PEEK capillary showed that the aperture vibrationscould be reduced in size and amplitude and hence increases the range ofsingle drop stability. The modulus of elasticity for borosilicate isabout 9×10⁶ psi whereas the modulus of elasticity for PEEK is in therange of about 0.6 to 1.5×10⁶ psi. Hence, the PEEK should dampen thecapillary oscillations due the piezo actuation and provide dropstability over a larger volume range. This was shown to be the case forthe experimentally measured stable single drop range with the 100 micronapertures. The 100 micron aperture provided an improved stable droprange of 200 to 500 pL. See Table II below. However, it was observedthat the improvement in the stable drop range seen with PEEK tended tovary between different capillary tubes. The variability of the stabledrop range between capillary tubes was found to result from variation inthe ball/springe clamp mechanism, in that it was difficult toconsistently maintain a constant spring tension within the headassembly. This variability can be readily appreciated from FIG. 15, inwhich the data from Table II is plotted.

TABLE II Trial Voltage Volume 1 55 V 233 pL 60 V 248 pL 65 V 255 pL 70 V302 pL 72 V 306 pL 2 56 V 234 pL 60 V 250 pL 65 V 257 pL 70 V 280 pL 71V 281 pL 3 63 V 380 pL 65 V 403 pL 70 V 469 pL 75 V 536 pL 4 65 V 208 pL75 V 237 pL 80 V 259 pL 85 V 285 pL 90 V 299 pL 95 V 316 pL 100 V  317pL 5 75 V 220 pL 80 V 243 pL 85 V 264 pL 90 V 286 pL 95 V 298 pL

III. Configuration:

PEEK capillary: Double V Clamp

100 um sapphire apertures

Reagent: BSA, DNA

Voltage only

In order to improve the variability of the stable drop range the PEEKcapillary system was evaluated with the double V clamp as shown in FIG.4B, but without the sleeve around the PEEK capillary. The double V clampprovides an operative coupling between the piezoelectric actuator andthe capillary tube, in which the coupling is configured to allowreplacement of capillary tubes and is adjustable to provide sufficientmechanical stability to reduce variations in droplet volumes betweencapillary tubes. The result was that the variability between capillarieswas substantially improved and even just as important, the stable dropvolume range was substantially improved to 80 pL up to about 1300 pL fora 100 micron aperture using adjustments of the piezoelectric elementdrive voltage. See Table III below. Stable drop volume and reducedvariations between capillary tubes can be appreciated from FIG. 16, inwhich the data from Table III is plotted. The major surprise is that thestable drop range was obtainable over a factor 13 in drop volume using asingle aperture size. Using an 80 micron aperture size a similar droprange was also achievable. The piezoelectric element drive voltage wasthe independent variable for controlling the drop volume. In general,with classical piezoelectric dispensing, the aperture size has beenimportant to achieving a volume range, where small apertures in the50-60 micron range are required to dispense 100-200 pL drops, and largerapertures in the range of 80-100 microns are required to achieve dropsizes up into the 800 pL range. This is a new, important and unexpectedresult.

A second important discovery was that a wide range of reagents could bedispensed with no special treatments of the apertures. This includedDNA, proteins, etc.

TABLE III Trial Voltage Volume 1 44.8 V   154 49 V 208 56 V 269 63 V 29870 V 346 77 V 392 84 V 411 91 V 445 98 V 478 105 V  500 112 V  522 117.6V   532 2 44.8 V   174 49 V 200 56 V 264 63 V 346 70 V 406 77 V 475 84 V525 91 V 562 95.2 V   615 3 42 V 140 49 V 181 56 V 245 63 V 325 70 V 39077 V 414 84 V 465 91 V 482 98 V 513 4 49 V 150 56 V 212 63 V 275 70 V332 77 V 369 84 V 396 91 V 425 98 V 455 105 V  482 106.4 V   486 5 44.8V   176 49 V 203 56 V 259 63 V 329 70 V 389 77 V 437 84 V 505 91 V 54295.2 V   563 *Table above demonstrates improved stability with thedouble V clamp. Low end and high end volume ranges are not includedbecause of the need to adjust both voltage and charge resistor.

IV. Configuration

PEEK capillary: Double V Clamp

100 um sapphire apertures

Reagents: solutions of DNA and protein antibodies in glycerol up to 60%glycerol

Voltage coupled with Charge resistor

A third important discovery was that once the drop size stability wasestablished the influence of the charge resistor value was investigatedand found to be important in controlling the ability to deal withdispensing of reagents with different rheology properties such asglycerol. For example it was shown that different concentrations of anaqueous reagent with a viscous buffer like glycerol could be dispensedby using the charge resistor control on the piezoelectric element incombination with the drive voltage. See Table IV below. Using fastercharge times enabled higher viscosities to be efficiently dispensed.Even more important is that a series of dilutions could all be dispensedat the same volume using the charge resistor control function. Theeffect of the charge resistor is to increase the acceleration of thepiezoelectric element in shearing the fluid within the capillary thusproviding increase flow velocity of the viscous reagent through theaperture.

TABLE IV Percent Glycerol Voltage Charge Resistor Volume 0 50 V 15.5 Ω270 pL 20 52 V 10.5 Ω 285 pL 40 56 V   7 Ω 283 pL 60 71 V  5.5 Ω 286 pL70 70 V   1 Ω 326 pL

Any of the methods which are described and illustrated herein are notlimited to the sequence of acts described, nor are they necessarilylimited to the practice of all of the acts set forth. Other sequences ofacts, or less than all of the acts, or simultaneous occurrence of theacts, may be utilized in practicing embodiments.

It is to be understood that any range of values disclosed, taught orsuggested herein comprises all values and sub-ranges therebetween. Forexample, a range from 5 to 10 will comprise all numerical values between5 and 10 and all sub-ranges between 5 and 10.

From the foregoing description, it will be appreciated that a novelapproach for dispensing (and aspirating) of micro-volumes of fluids hasbeen disclosed. While the components, techniques and aspects ofembodiment have been described with a certain degree of particularity,it is manifest that many changes may be made in the specific designs,constructions and methodology herein above described without departingfrom the spirit and scope of this disclosure.

While a number of embodiments and variations thereof have been describedin detail, other modifications and methods of using and diagnostic,assaying, arraying, medical, biotech and printing applications for thesame will be apparent to those of skill in the art. Accordingly, itshould be understood that various applications, modifications, andsubstitutions may be made of equivalents without departing from thespirit of the disclosure or the scope of the claims.

Various modifications and applications of disclosed embodiments mayoccur to those who are skilled in the art, without departing from thetrue spirit or scope of the disclosure. It should be understood that thedisclosure is not limited to the embodiments set forth herein forpurposes of exemplification, but is to be defined only by a fair readingof the appended claims, including the full range of equivalency to whicheach element thereof is entitled.

1. A dispenser for transferring a predetermined quantity of a liquid,comprising: a longitudinal transducer, comprising: a capillary tubehaving a tip at a distal end of the capillary tube; a piezoelectricactuator operatively coupled to the capillary tube at a locationproximal of the tip; an aperture at the tip of the tube; and a flexiblesupply line located upstream of the capillary tube and configured tocouple to and supply the liquid to the capillary tube; wherein actuationof the piezoelectric actuator causes a pressure wave to propagate fromsaid location of the capillary tube toward the tip of the capillary tubesuch that radial motion at said location of the capillary tube istransmitted as distally extending axial motion of the tip of thecapillary tube, thereby causing a droplet of a predetermined volume tobe ejected from the aperture; wherein the capillary tube has a modulusof elasticity in a range of about 0.1 to 1.5×10⁶ psi, thereby dampeningacoustical noise from the actuation and providing single drop stabilityover a range of drop sizes from about 50 to 1300 pL.
 2. The dispenser ofclaim 1, wherein the coupling between the capillary tube and theflexible supply line provides a self-aligning feature.
 3. The dispenserof claim 1, wherein the operative coupling between the capillary tubeand the piezoelectric actuator is configured to allow replacement ofcapillary tubes and is adjustable to provide sufficient mechanicalstability to reduce variations in droplet volumes between capillarytubes.
 4. The dispenser of claim 1, wherein the operative couplingbetween the capillary tube and the piezoelectric actuator is a double Vclamp.
 5. The dispenser of claim 1, wherein the capillary tube comprisespolyether ether ketone (PEEK).
 6. The dispenser of claim 1, wherein thecapillary tube comprises an aperture plate that defines the aperture. 7.The dispenser of claim 6, wherein the aperture plate is gold-platednickel or sapphire.
 8. A method of transferring a predetermined quantityof a liquid, comprising: coupling a flexible supply line to a capillarytube using a self-aligning feature; supplying liquid from the flexiblesupply line to the capillary tube, wherein the capillary tube comprisesa distal end with a tip and an aperture thereat; coupling apiezoelectric actuator to the capillary tube at a location along thecapillary tube, wherein the coupling between the piezoelectric actuatorand the capillary tube is configured to allow replacement of capillarytubes and is adjustable to provide substantially uniform mechanicalstability between the piezoelectric actuator and replaceable capillarytubes; actuating the piezoelectric actuator such that a pressure wavepropagates from said location along the capillary tube toward the tip ofthe capillary tube and radial motion at said location is transmitted asaxial motion of the tip, thereby causing a droplet of a predeterminedvolume to be ejected from the aperture; wherein the capillary tube has amodulus of elasticity in a range of about 0.1 to 1.5×10⁶ psi, therebydampening acoustical noise from the actuation and providing single dropstability over a range of drop sizes from about 50 to 1300 pL.
 9. Themethod of claim 8, further comprising adjusting the coupling between thepiezoelectric actuator and the capillary tube to reduce variation indroplet volume between capillary tubes.
 10. The method of claim 8,further comprising adjusting a piezoelectric voltage, a charge resistor,or both a voltage and a charge resistor to enable dispensing a range ofliquid viscosities at the same predetermined droplet volumes.